HIV infection of human cells depends on fusion of the HIV viral membrane with the target human cell membrane. The fusion process involves multiple proteins involved in viral recognition of the human cell, with fusion mediated by the protein gp41, which undergoes a conformational change to a six-helix bundle (trimer of hairpins) that is necessary for membrane fusion to occur. It has long been recognized that preventing trimer-of-hairpins formation, via binding to the three-stranded coiled coil of gp41, can be an effective strategy in preventing HIV infection of cells. Indeed, this mechanism is the basis of effectiveness of the anti-HIV peptide drug Fuzeon. However, Fuzeon currently has limited applications due to the challenges of peptide-based drugs, including large synthetic (materials) cost of the 36 amino acid peptide and the inability to use oral delivery. These challenges could be overcome by small molecules that function equivalently to the Fuzeon protein, via disruption of the gp41 intramolecular protein-protein interactions. Herein, we will develop small molecule inhibitors of gp41 trimer-or-hairpins formation via the development of small molecule alpha-helical proteomimetics, which mimic the presentation of side chains in the hydrophobic core of gp41. These inhibitors will be examined for their ability to prevent gp41 trimer of hairpins formation, a monomeric agents and and multivalent agents. This work promised to develop novel, highly potent inhibitors of gp41 trimer-of-hairpins formation that could be extended to be novel small molecule HIV fusion inhibitors.